E2F-1 overexpression in cardiomyocytes induces downregulation of p21CIP1 and p27KIP1 and release of active cyclin-dependent kinases in the presence of insulin-like growth factor I

Circ Res. 1999 Jul 23;85(2):128-36. doi: 10.1161/01.res.85.2.128.

Abstract

The heart is a postmitotic organ unable to regenerate after injury. The mechanisms controlling cell cycle arrest in cardiomyocytes are still unknown. Adenoviral delivery of E2F-1 to primary rat cardiomyocytes resulted in an increase in the expression of key cell cycle activators and apoptosis in >90% of the cells. However, insulin-like growth factor I (IGF-I) rescued cardiomyocytes from E2F-1-induced apoptosis. Furthermore, overexpression of E2F-1 in the presence of IGF-I induced the specific downregulation of total p21(CIP1) and p27(KIP1) protein levels and their dissociation from cyclin-dependent kinases (cdks). In contrast, p16(INK4) and p57(KIP2) protein levels and their association with cdks remained unaltered. The dissociation of p21(CIP1) and p27(KIP1) from their cdk complexes correlated well with the activation of cdk2, cdk4, and cdk6 and the release from cell cycle arrest. Under these circumstances, the number of cardiomyocytes in S phase rose from 1.2% to 23%. These results indicate that IGF-I renders cardiomyocytes permissive for cell cycle reentry. Finally, the specific downregulation of p21(CIP1) and p27(KIP1) further suggests their key role in the maintenance of cell cycle arrest in cardiomyocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae
  • Animals
  • Apoptosis / physiology
  • Carrier Proteins*
  • Cell Cycle Proteins / genetics
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclin-Dependent Kinases / metabolism*
  • Cyclins / genetics*
  • Cyclins / metabolism
  • DNA-Binding Proteins*
  • Down-Regulation / drug effects
  • Down-Regulation / physiology
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Gene Expression / physiology
  • In Situ Nick-End Labeling
  • Insulin-Like Growth Factor I / pharmacology*
  • Microtubule-Associated Proteins / genetics*
  • Microtubule-Associated Proteins / metabolism
  • Muscle Fibers, Skeletal / cytology
  • Muscle Fibers, Skeletal / metabolism
  • Myocardium / cytology
  • Myocardium / metabolism*
  • Phosphorylation
  • Rats
  • Rats, Wistar
  • Recombinant Fusion Proteins / genetics
  • Retinoblastoma Protein / metabolism
  • Retinoblastoma-Binding Protein 1
  • S Phase / physiology
  • Transcription Factor DP1
  • Transcription Factors / genetics*
  • Tumor Suppressor Proteins*

Substances

  • Carrier Proteins
  • Cdkn1a protein, rat
  • Cdkn1b protein, rat
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • DNA-Binding Proteins
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • E2f1 protein, rat
  • Microtubule-Associated Proteins
  • Recombinant Fusion Proteins
  • Retinoblastoma Protein
  • Retinoblastoma-Binding Protein 1
  • Transcription Factor DP1
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • Insulin-Like Growth Factor I
  • Cyclin-Dependent Kinases